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|Ref Type||Journal Article|
|Authors||Narita Y, Okamoto K, Kawada MI, Takase K, Minoshima Y, Kodama K, Iwata M, Miyamoto N, Sawada K|
|Title||Novel ATP-competitive MEK inhibitor E6201 is effective against vemurafenib-resistant melanoma harboring the MEK1-C121S mutation in a preclinical model.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||Many clinical cases of acquired resistance to the BRAF inhibitor vemurafenib have recently been reported. One of the causes of this acquired resistance is the BRAF downstream kinase point mutation MEK1-C121S. This mutation confers resistance to not only vemurafenib, but also to the allosteric MEK inhibitor selumetinib (AZD6244). Here, we investigated the pharmacologic activities and effectiveness of the novel MEK inhibitor E6201 against BRAF (v-raf murine sarcoma viral oncogene homolog B1)-V600E mutant melanoma harboring the MEK1-C121S mutation. A cell-free assay confirmed that E6201 is an ATP-competitive MEK inhibitor, meaning it has a different binding mode with MEK compared with allosteric MEK inhibitors. E6201 is more effective against BRAF-V600E mutant melanoma compared with BRAF wild-type melanoma based on MEK inhibition. We found that the acquired MEK1-C121S mutation in BRAF-V600E mutant melanoma conferred resistance to both vemurafenib and selumetinib but not E6201. The effectiveness of E6201 in this preclinical study is a result of its binding with MEK1 far from the C121S point mutation so the mutation is unable to influence the MAPK pathway inhibitory activity. These results support further clinical investigation of E6201.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|MAP2K1||C121S||missense||gain of function||MAP2K1 C121S lies within the protein kinase domain of the Map2k1 protein (UniProt.org). C121S confers a gain of function on the Map2k1 protein as demonstrated by increased Erk1/2 (PMID: 25899310) and Mek phosphorylation in culture and has been demonstrated to confer acquired resistance to Raf and Mek inhibitors (PMID: 21383288, PMID: 24448821, PMID: 29483135, PMID: 29753091).||Y|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|BRAF V600E MAP2K1 C121S||melanoma||decreased response||Selumetinib||Preclinical||Actionable||In a preclinical study, melanoma cell lines harboring BRAF V600E mutation and overexpressing MAP2K1 C121S were less sensitive than those overexpressing wild-type MAP2K1 to Selumetinib (AZD6244)-induced inhibition of Mapk pathway activation and cell proliferation in culture (PMID: 24448821).||24448821|
|BRAF V600E MAP2K1 C121S||melanoma||sensitive||E6201||Preclinical||Actionable||In a preclinical study, E6201 inhibited Mapk pathway activation and proliferation of melanoma cell line harboring BRAF V600E mutation and overexpressing MAP2K1 C121S in culture (PMID: 24448821).||24448821|
|BRAF V600E||melanoma||sensitive||E6201||Preclinical||Actionable||In a preclinical study, E6201 inhibited Mapk pathway activation and proliferation of melanoma cell lines harboring BRAF V600E mutation in culture (PMID: 24448821).||24448821|
|BRAF V600E MAP2K1 C121S||melanoma||resistant||Vemurafenib||Preclinical - Cell culture||Actionable||In a preclinical study, expression of MAP2K1 C121S conferred resistance to Zelboraf (vemurafenib) in melanoma cell lines harboring BRAF V600, resulting in decreased sensitivity to Zelboraf (vemurafenib)-induced inhibition of MAPK pathway activation and cell proliferation in culture (PMID: 24448821).||24448821|